Mitochondria are dynamic organelles that consistently undergo fission and fusion events. Deficiencies in the proteins regulating mitochondrial dynamics are associated with a number of human pathologies including neurodegenerative diseases and newborn lethality (Westermann, 2010). Recently, mitochondria have been shown to undergo morphological remodeling as cells progress through the cell cycle (Mitra et al., 2009). At the G1/S boundary mitochondrial tubules form a highly fused network, which is associated with increased mitochondrial ATP production and high levels of cyclin E, in order to promote G1-to-S transition (Mitra et al., 2009). This hyperfused mitochondrial network is then disassembled and becomes increasingly fragmented through S, G2 and M phase of the cell cycle, with the greatest fragmentation evident during mitosis in order to allow the proper partitioning of mitochondria between two daughter cells during cytokinesis (Kashatus et al., 2011). Thus, mitochondrial remodeling throughout the cell cycle is considered to meet the cellular energy demands during the progression of specific stages of the cell cycle, and to ensure faithful inheritance of mitochondria during cell division. However, how deficiencies in the proteins that regulate mitochondrial dynamics impact cell cycle progression and hence directly contribute to the development of diseases is not clear.
The dynamic regulation of mitochondrial morphology is achieved by the coordination of mitochondrial fission and fusion events (Green and Van Houten, 2011). Dynamin-related protein 1 (Drp1), a large dynamin-related GTPase, is essential for mitochondrial fission (Smimrnova et al., 2001). Loss of Drp1 results in elongated mitochondria, and Drp1 deficiencies have been identified in several human diseases (Cho et al., 2009; Wang et al., 2008; Waterham et al., 2007). Drp1 is directly regulated by the machinery that controls cell cycle progression. For example, Drp1 is phosphorylated at Ser585 by cdc2/cyclin B in order to promote mitochondrial fission during mitosis (Taguchi et al., 2007). Drp1 deficiency is generally thought to cause mitochondrial dysfunction due to a failure of a Drp1-dependent mechanism of mitophagy that removes damaged mitochondria within the cell (Twig et al., 2008). The resulting accumulation of damaged mitochondria may lead to a depletion of cellular ATP and an inhibition of cell proliferation (Parone et al., 2008). Such an energy depletion-related cell proliferation defect may be caused by a metabolic checkpoint that triggers an AMPK- and p53-dependent G1/S cell cycle arrest (Jones et al., 2005; Owusu-Ansah et al., 2008). Consistent with such a mechanism, overexpression of mutant Drp1 (K38A), results in a hyperfused mitochondrial network and a p53-dependent delay of S phase entry (Mitra et al., 2009). However, reduced cell proliferation has also been observed in the absence of cellular ATP depletion in non-immortalized Drp1-knockout mouse embryonic fibroblasts (MEFs) (Wakabayashi et al., 2009). This suggests that defective mitochondrial dynamics may affect cell proliferation through mechanisms that are not associated with mitochondrial energy metabolism.
Chiang et al. (2009) studied Drp-1 in lung adenocarcinoma, and report a link between Drp 1 and chemotherapy drug resistance that is related to intracellular distribution of Drp 1, where sequestration of Drp 1 to the nucleus (which may be related to hypoxia) is associated with resistance to chemotherapy and poor prognosis.
United States Patent Application Publication Nos. US2005/0038051 and US2008/0287473, both by Nunnari et al., disclose mdivi-1 (referred to as compound A1 and mfisi-1 therein) and related compounds. These applications also disclose that mdivi-1 is a selective inhibitor of Dnm1, the yeast ortholog of Drp1, and inhibits mitochondrial fission and apoptosis. Further, a polypeptide antagonist of calcineurin was reported to inhibit Drp1-dependent mitochondrial fragmentation and apoptosis (Cereghetti and Scorrano, 2010).